Venlafaxine is a new generation antidepression drug, first introduced in 1993. It is used for the treatment of major depressive disorder (MDD), as a treatment for generalized anxiety disorder, and co-morbid indications in certain anxiety disorders with depression. In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions. Although venlafaxine is sold as a racemate, (−)-venlafaxine is a more potent inhibitor of norepinephrine synaptosomal uptake while (+)-venlafaxine is more selective in serotonin uptake. It is different from other antidepressants in that it has no or little activity on a variety of neuroreceptors. (e.g. α OR β-adrenergic receptors, muscarinic receptors, cholinergic receptors, histaminic receptors etc.).
There are number of racemic syntheses reported for venlafaxine, including those by the inventors. These synthetic routes for racemic venlafaxine mainly involve the condensation of cyclohexanones with 4-methoxyphenyl acetic acids or 4-methoxyphenyl acetonitriles followed by functional group manipulation.
As both enantiomers possess different biological activities, therefore asymmetric synthesis of Venlafaxine is a subject matter of interest.
Nanda et al in Tetrahedron Letters 53 (2012) 1990-1992 reported an enzyme based resolution for asymmetric synthesis of venlafaxine. Their strategy included (S)-HNL catalyzed synthesis of cyanohydrins from cyclic ketones and lipase-PS catalyzed kinetic resolution for creation of the stereocenter.
Chem. Commun., 2006, 3110-3112 disclose β-Amino esters which are readily formed from rhodium(II) prolinate-catalyzed intermolecular C—H insertion between methyl aryldiazoacetates and a bis-silyl protected methylamine. This was applied for effective synthesis of venlafaxine with enantiomers obtained with moderate yields moderate % ee.
But prior art methods suffer from the main drawback of having to resolve the enantiomers in a separate dedicated step, and yet result in only moderate yield. Also, these processes employ hazardous and potentially explosive reagents. They need dry, inert conditions during use of Grignard's reagent and many processes need cryogenic conditions. Also, these prior art processes use metal based catalyst which are not environmentally friendly.